1. Field of the Invention
The present invention relates to an improved process for the preparation of an intermediate useful for the manufacture of gefitinib. In particular, the present invention relates to a chemical process for the preparation of a quinazoline derivative of formula A given below:
where P represents a hydrogen, 3-(morpholinyl)propyl or a hydroxyl-protecting group.
2. Description of the Related Art
Gefitinib is an anilinoquinazoline with the chemical name N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine and the following structural formula I:
Gefitinib is marketed with a brand name of IRESSA by AstraZeneca Pharmaceuticals LP, indicated as monotherapy for continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies who are benefiting or have benefited from IRESSA (gefitinib).
Gefitinib is the first selective inhibit of epidermal growth factor receptor's (EGFR) tyrosine kinase domain. It was first disclosed in International Patent Application No. WO 96/33980 and U.S. Pat. No. 5,770,599. The process disclosed is depicted in the following scheme 3. The process of preparing gefitinib disclosed in this patent application involves using methanesulfonic acid and L-methionine in the selective demethylation of 6,7-dimethoxy-3H-quinazolin-4-one to obtain the 6-hydroxyl derivative. Afterwards, the hydroxyl moiety is protected by acylating the 6-hydroxyl moiety, followed by reacting the 6-acylated derivative with thionyl chloride to obtain the chloro derivative, which is then condensed with 3-chloro-4-fluoroaniline. The resulting intermediate is hydrolyzed, and then etherified with 3-morphorlinopropyl chloride to give crude gefitinib which is further purified by column chromatography.

With regard to the above process, the intermediate of Formula VII was prepared from 6,7-dimethoxyquinazolin-4(3H)-one through five steps, containing selective removal of methyl group at C6 with L-methionine in the presence of methane sulfonic acid, acetylation, chlorination, SNAr reaction and deacetylation. Such a process suffers from several disadvantages in the preparation of gefitinib. One of the major disadvantages is that it involves removing methyl group of the starting material at C7 by the use of methane sulfonic acid and L-methionine in demethylation step. The selective demethylation results in the formation of isomeric impurities, which has to proceed with further purification, such as column chromatography, in the manufacture of gefitinib. The process also involves the use of thionyl chloride for chlorination in the manufacture of gefitinib. However, thionyl chloride is not environmentally friendly and is difficult to handle.
Indian Patent Application No. IN2005CH00219 reports a method of synthesizing 6-hydroxy-7-methoxy quinolin4-(3H)-one, and another method of converting 6-hydroxy-7-methoxy quinolin4-(3H)-one to gefitinib through an intermediate of formula VII. The process reported is depicted in the following scheme 4. Specifically, the process involves using a compound of formula IV to prepare the intermediate of formula VII useful for the preparation of gefitinib via passing through the intermediates of formulae XI-XIV as shown below. However, the process has a major disadvantage, in the preparation of the intermediate of formula VII, which is still not concise enough because the cyclization of reacting 4,5-substituted 2-amino-benzamide (XI) with HCOOH to give the quinazolin-4-one of formula XII results in the subsequent long-winded steps in the preparation of the intermediate of formula VII.

Chinese Patent No. CN100420676C discloses a process for preparing the intermediate of formula VII useful for the manufacture of gefitinib. The process disclosed in CN100420676C is depicted in the following scheme 5. The process involves the use of 6,7-substituted quinazolin-4-one (XII) in the preparation of the intermediate of formula VII via passing through intermediates of formulae XV and X as shown below. In comparison with the process disclosed in IN2005CH00219, the process merely changes chemical reaction orders of synthesizing the compound of formula VII beginning with the compound of formula XII. Thus, the number of reaction steps is not reduced at all. Although this patent does not report how to obtain the compound of Formula XII, it is very likely that the compound of Formula XII could be obtained from the compound of formula IV from a chemical perspective. Therefore, this process does not provide a more efficient synthetic route to remedy the drawback of the process disclosed in IN2005CH00219.

Indian Patent Application No. IN2006CH00901 reports a process for the synthesis of gefitinib. The process disclosed in IN2006CH00901 is depicted in the following scheme 6. This process principally involves converting the compound of formula XVI into an oxime and dehydrating of the oxime to obtain the compound of formula XVII, followed by proceeding with the reactions of nitration, reduction and amidine formation to obtain the compound of formula XX, and then the compound of formula XX is isolated as an oily intermediate by evaporation for the preparation of gefitinib. Although the process disclosed in this patent application is a more efficient process for the synthesis of gefitinib because of the reduction of the number of steps, there is a significant drawback that all intermediates must be isolated in the processing procedure. It is not beneficial in terms of cost and time.

Chinese Patent Application No. CN101402610A discloses a synthesis of gefitinib. The process disclosed in CN101402610A is depicted in the following scheme 7. The process involves a cyclization of a compound of formula XIX with a compound of formula XXI prepared from 3-chloro-4-fluoroaniline to synthesize gefitinib. However, this process still needs to isolate the compound of formula XXI first before reacting with the compound of formula XIX. That is a more complicated procedure.

Given the above, there is a need for a more direct and less laborious process for preparing the intermediate of formula VII useful for the manufacture of gefitinib.